Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Loss of TGFBR3 in ovarian cancers reduces sensitivity to chemotherapeutics and enhances cancer stem cell marker expression (#97)

Maree Bilandzic 1 , Yao Wang 1 , Jock K Findlay 1 , Kaye L Stenvers 1
  1. Prince Henry's Insitute , Clayton, VIC, Australia

Type III TGF-beta receptor (TGFBR3; betaglycan) expression is significantly reduced in the majority of advanced stage serous epithelial ovarian cancers and granulosa cell tumours (GCTs), with increasing loss correlated with disease progression (Bilandzic et al., 2009, Mol Endocrinol 23:539-548; Hempel et al., 2007, Cancer Res 67:5231-5238). In this study, we tested the hypothesis that loss of TGFBR3 by GCTs contributes to their acquisition of chemoresistance. Using MTT cell viability assays, we examined the effect of TGFBR3 on the response of the KGN GCT line to the chemotherapeutic, cisplatin. Comparison of IC50 values for cisplatin showed that monolayer cultures of TGFBR3-expressing KGN were 4-fold (p<0.0001) more sensitive to cisplatin compared to controls. Similarly, spheroid culture experiments demonstrated a significant 2-fold decrease in viability from 2-5 d in TGFBR3-expressing spheroids compared to controls (p<0.05). Acquisition of chemoresistance by ovarian cancer cells has been previously associated with the presence of a 'cancer stem cell' (CSC) population, which is capable of surviving initial chemotherapy (Bapat SA et al., Cancer Research 65 3025–3029.). Therefore, we determined the levels of the stem cell markers NANOG, WNT1, CD44, and OCT4 in the KGN cell line by RT-PCR analysis in response to cisplatin treatment. Under basal conditions, TGFBR3 and control cells maintained similar levels of the CSC markers. Following 5 d cisplatin treatment, significant increases (p<0.0001) in WNT1, OCT4, NANOG, and CD44 were observed in the control cells, but not the TGFBR3-expressing cells. Collectively, these data suggest that the loss of TGFBR3 expression in advanced, metastatic ovarian cancers is linked to the acquisition of chemoresistance. Additionally, loss of TGFBR3 expression in ovarian cancers may enhance stem cell-like features, which underlies their reduced sensitivity to chemotherapeutics and their increased capacity for tumour recurrence. Supported by the NHMRC of Australia (RegKeys 494802; 441101; 388904) and Victorian Government Infrastructure funds.